JPH06502658A - dihydroxyindanone compound - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] cyhydroxyindanone tyrosine kinase inhibitor The present invention is useful for cancer, anti-tumor tube formation, and didiamine, a tyrosine kinase inhibitor useful in controlling atherosclerosis. This invention relates to hydroxyindanone compounds.

Background of the invention Tyrosine-specific protein kinase (tyrosine kinase) A type that catalyzes the transfer of the terminal phosphate of adenosine triphosphate to a tyrosine residue in It is an enzyme. The first of its kind to be identified was a cell transformation Tyrosine kinases associated with viral genes (called oncogenes) that can be (i.e., pp60v-src and pp98r-fps). after that , the normal cellular counterparts to these viral gene products (i.e., ppao c-src and pp98cmfps). confirmed ciro A third type of synkinase is called a growth factor receptor, which includes Includes insulin, epithelial epidermis and p185HER-2 receptor. these Both tyrosine kinases signal many cellular functions by phosphorylating their substrates. It is thought to play an important role in transduction.

Although the exact mechanism of signal transduction is still unclear, tyrosine kinase has been shown to be an important contributing factor in cell proliferation, carcinogenesis, and cell differentiation. ing. Therefore, inhibitors of these tyrosine kinases inhibit the activation of these enzymes. It is useful in proliferative disease prevention and chemotherapy.

Summary of the invention The present invention provides dihydroxyindanone compounds useful as tyrosine kinase inhibitors. Regarding. The compound of the present invention is a compound represented by the following formula and its pharmaceutically acceptable compound. salts and prodrugs: (In the formula, R1 is H1 alkyl (CI-C6) or phenyl; R5 is phenyl, phenyl; phenylalkyl (CI-C3), NH-phenyl, hydroxyphenyl, - (C,-C4)alkyl or chenyl: R6 is (CI-Cs)alkyl , nitro, perhaloalkyl (CI CJ, 710, R2 is H, halo, bellhalo Alkyl (CI-C4), alkoxy (C, -C,), However, at least two of R2, R3 or R4 are H, and R3 and and R4 is H, R2 cannot be H).

A first group of preferred compounds of formula r are compounds where R2 and R4 are H .

Among this first preferred group, compounds in which R3 is halo are particularly preferred. be. Among this latter group, preferred are those in which R7 is H, halo, trifluoro A compound that is methyl or methoxy.

A second group of preferred compounds of formula I are compounds of R2 and R3 or H .

Particularly preferred within this second preferred group are those in which R2 is phenyl or n -butyl compound.

A third group of preferred compounds of formula I are compounds where R1 and R4 are H .

A particularly preferred first group of compounds within this third preferred group is R2 or halo, N　O2, -CO□alkyl (CI-C4) or C○○H It is a thing. A second particularly preferred group of compounds of formula r The best option is for Rs to be phenyl, phenethyl, -NH-phenyl, hydroxyphenyl. A compound that is phenyl, propyl or thiophene. Favorite among this group Preferably, R5 is phenyl, phenethyl, -NH-phenyl, 2-hydroxy Compounds that are phenyl, propyl or 3-thiophene. of the compound of formula ■ A particularly preferred third group of compounds within this third preferred group is R 2 is a compound. Among this latter group, preferred are those in which R2 is It is a compound that Among this latter group, preferred are those in which R6 is t-butyl; Compounds that are nitro, trifluoromethyl, -8O□-methyl or H.

A fourth group of particularly preferred compounds within this third preferred group of formula ■ Is it R2? It is a compound that is Preferred within this latter group are those in which R2 is It is a compound. Preferred within this latter group are those in which R6 is t-butyl. In addition, tyrosinase in mammals containing a compound of formula (■) in a pharmaceutically acceptable carrier. Pharmaceutical compositions for inhibiting diseases caused by tyrosine kinases: In mammals suffering from diseases caused by tyrosine kinases, doses that inhibit diseases caused by tyrosine kinases Suppressing diseases caused by tyrosine kinases, consisting of administering a compound of the formula It is about the method.

The expression "pharmaceutically acceptable cationic salts" refers to non-toxic cationic salts, e.g. but not limited to] sodium, potassium, calcium, magnesium Ammonium or protonated benzathine (diamine), choline, ethanolamine, jetanolamine, ethylenethia amine, megramino (N-methylglucamine), henetamine (N-hensilphene) thylamin) piverane or tromethamine (2-amino-2-hydroxymethylene) (1,3-propanediol).

The expression "prodrafugu" means that following administration and absorption, certain metabolic processes refers to compounds that are drug precursors that release drugs in vivo. Example of Prodraftfish are alkyl ethers, acyl esters and acid esters of phenolic compounds, For example, methyl ether, esters of alkanoic acids (CI-CIO) and formulas (acids, ester) group) and formula Other features and features will become apparent from the description and claims. Probably.

Detailed description of the invention Reaction formula [ Reaction formula■ Reaction formula■ According to Scheme I, a compound of formula ■ where R and R5 are alkyl (C,-C,) is reduced from a suitable compound of formula ■ where R and R1 are alkyl (Cj C4) It can be manufactured by

Generally, a compound of formula (1) is prepared in the presence of a noble metal catalyst at a pressure of 20-50 psi and at ambient temperature. Reduction by exposure to hydrogen for 2-24 hours at 100°C to 100°C. in general , the compound of formula ■ is prepared in a solvent such as alcohol or tetrahydrofuran. Ru.

Alternatively, a compound of formula (II) may be prepared by protonation, such as acetic acid, at ambient temperature and pressure of 100'C1. Reduction can be performed using metals such as zinc or iron in a neutral solvent for 0.5-4 hours.

Furthermore, compounds of formula IVA where R and R1 are H, .

-C4), deprotection of a compound of formula H to a compound of formula is formed by deprotection in a manner similar to that described above for .

Compounds of formula Ⅰ, where R and R, are alkyl (CI-C4) according to reaction scheme I is cyclized from a suitable compound of formula V where R and R1 are alkyl (C,-C,) (i.e. Friedel Krach). In general, compounds of formula ■ The substance is reacted with a Lewis acid catalyst such as BF3, mineral acid or polyphosphonic acid in the absence of a solvent. Expose at ambient temperature to 100'C.

R and R3 are alkyl (CI C4), R3 and R1 are Hl and R2 or and R1 is alkyl (CI C4) and carbonyl (in R2) is its reduction (i.e., hydroxy) by oxidation. Can be manufactured.

Generally, a compound of formula ■ is prepared in a pyridine sulfur trioxide complex and a solvent such as DMSO. React in the presence of trialkylamine at a temperature of 0°C to 50°C for 30 minutes to 2 hours. oxidize by

According to the reaction formula (■), R and Ro are alkyl (CI C4) and carbonyl A compound of formula ■ present (within R2) or in its reduced form (i.e. hydroxy) is , R and R, or alkyl (C, -C4), from a compound of formula and condensation with suitable aldehydes.

Generally, the compound of formula aryl or alkyl metal base at −78°C to OoC. The metallogen exchange is carried out in a cell at ambient pressure for 30 minutes to 2 hours. Then organic A metal compound is mixed with a suitable aldehyde in the above solvent at a temperature of -78°C to OoC for 1 -Condense for 4 hours.

According to the reaction formula (■), R and R are alkyl (C, -C,), and R2 or -COOH, where R and R1 are alkyl (CI-C4) From the compound of formula ■, which is, the compound of formula ■ is obtained by using CO2 instead of aldehyde. It can be produced in a similar manner to the above conversion of the compound to the compound of formula (1).

Compounds of formula Ⅰ, where R and R1 are alkyl (CI-C4) according to reaction formula H is prepared from a suitable compound of formula ■ by protecting the carbonyl functionality. sell.

Generally, compounds of formula of toluenesulfonic acid in non-hydroxyl or hydrocarbon solvents such as aromatics. The reaction is carried out in the presence of a catalytic acid such as, and water is removed at the same time. In general, the reaction Perform at ambient pressure and reflux conditions.

According to reaction formula ①, R and R1 are trimethylsilyl (TMSO), Rz and and R1 is H and R3 is Compounds of formula It can be manufactured depending on the combination.

Generally, compounds of formula (d) at -78°C to 0°C. Exposure in hydroxyl solvent for 0.5-1 hour. Then, the obtained compound is React with aldehyde at -78°C to 0°C for 1-6 hours.

According to the reaction formula (■), R and R, or T M SO, R2 and R4, or H and Is a compound of formula H which is an anru as defined above a suitable compound of formula X? , as used above except that an acylating agent is used instead of the aldehyde condensation. It can be manufactured using a similar procedure. Generally, acylation is performed with acids such as halides or anhydrides. such as tetrahydrofuran at -78°C to OoC with a suitable activated acid. The reaction is carried out in a non-hydroxyl solvent for 1-6 hours.

According to the reaction formula ■, the compound of formula I can do it.

Generally, compounds of formula °C are prepared from alkoxy precursors using the deprotection conditions described above. . The resulting deprotected compound of formula °C is then treated as hexamethylsinlazan. silylating agent at 50'C-1506C in the absence of solvent for about 2 to about 12 hours. protect by making it compatible.

According to reaction formula (■), R and R1 or alkyl (C, -C,), R2 and R1 or Hl and R2 Compounds of formula (2) as defined above may contain R and R1 or alkyl (CI-〇,) can be prepared by catalytic conjugate addition from a compound of formula °C.

Generally, the compound of formula ■ is an organolithium reagent or an organomagnesium reagent. with an alkyl or aryl organometallic compound at -30°C to ambient temperature. React for 1-6 hours in an ethereal solvent such as hydrofuran. Generally, the reaction is Catalyzed with metal halides such as copper iodide (■).

Starting materials for the above reaction schemes (e.g., compounds of formula V, ■, °C and agents, sulfonating agents, aldehydes, organometallic compounds or amines) are conventional organic It can be easily synthesized by one skilled in the art starting from common chemical reagents using synthetic methods. It is possible.

The compounds of the invention are acidic and they form base salts. of such base salts. All are within the scope of this invention and can be manufactured by conventional methods. . For example, they contain acidic and basic entities, usually in stoichiometric proportions, in aqueous, non-aqueous or It can be easily produced by suitable contact in a partially aqueous medium or a partially aqueous medium. Ru. The salt is filtered or precipitated with a non-solvent before l! i! the solvent will evaporate. Appropriately collect it by either drying it or, in the case of an aqueous solution, by freeze-drying it. do.

Anlu prodrugs of the present phenolic compounds are organic amine bases (e.g. pyriprodrugs). A bicyclic phenolic compound is treated with an appropriate acid... It can be produced by acylation with anhydride. Estelle - Prodra 7g is one Can be prepared from acids by conventional esterification. Furthermore, the prodrug is the final compound can be produced without any deprotection.

All of the compounds of the present invention have been shown to be effective against tyrosine kinase-mediated diseases in mammals. It can be easily used therapeutically as a tyrosine kinase inhibitor. blood Diseases caused by rosine kinases are initiated by ectopic tyrosine kinase enzyme activity. / refers to a sustained hyperproliferative disease. Examples are cancer, atherosclerosis, These include anti-tumor tube formation (tumor growth, diabetic 11! membrane disease), etc.

In vitro tyrosine kinase inhibitory activity of compounds of the invention was determined based on standard procedures. It can be proven by a method. In one method, the enzyme pp60src is added to the inner surface of the plasma membrane. Tyrosine-specific phosphokinase (tyrosine kinase) associated with Rous sarcoma The virus is purified from cells of 7 cells that have been metastasized. In the basic analysis, Wong, T.

W., ,Goldberg, A., R., ,J., Biol,Chem, ,25th,. 8505-8512 (1984), the enzyme was incubated with a substrate with a total volume of 25 μm, v 3 for 25 minutes using a15 angiotensin ■ and gamma-32p-ATP. Incubate at 0°C. The reaction was started by adding 45 μl of 5% TCA. Stop, incubate on water for 5 minutes, and centrifuge for 1 minute to remove precipitated proteins. Excludes proteinaceous substances. Aliquot 35 μl of the supernatant solution into a phosphocellular paper circle. phosphoceLlular paper circle. Wash it three times with 0°5% H3P○, rinse with acetone, dry, and remove the liquid. Scintillation i, , J: Count. For screening, test compounds Incubate in incubation mixture of 25 μm: compound at 10 -4M, 10-5M and 10-6M and appropriate solvent controls for all analyses. Include in the body.

The compound may be administered orally or parenterally or topically as a straw; Approximately 0.1-40 mg/kg body weight per day is administered in divided doses. Of course, special In situation r, doses outside this range are used at the discretion of the examining physician.

The compounds of the invention can be administered in a variety of different dosage forms. In other words, this These can be combined with various chemically acceptable inert carriers to form tablets, capsules, and rosettes. Lozenges, pastilles, hard candy-1 powder, sprays, elixirs, lollipops, In the form of injections or eye drops, such carriers may include solid diluents or These include fillers, sterile aqueous media, and various non-toxic organic solvents.

For oral oN administration, various excipients such as sodium citrate, calcium carbonate and Calcium diphosphate is mixed with a dispersant such as starch, preferably starch or starch. pioca starch, alginic acid and certain complex silicates, and binders such as polymers. Contains along with ribinylpyrrolidone, sankarose, seratin and gum arabic. Use tablets. Additionally, lubricants such as magnesium stearate, lauryl Lithium sulfate and talc are often very useful in making tablets. same Similar types of solid compositions can also be used as fillers in soft and hard-filled Seratin capsules. I can stay. Preferred materials in this connection include lactose or milk sugar as well as polymers. Polyethylene glycol, etc. Aqueous 25 liquid and/or elixir When preferred for oral administration, the essential active ingredients therein may be combined with various sweetening agents, flavoring agents, and coloring agents. , emulsifying and/or suspending agents, and diluents such as water, ethanol, Mix with pyrene glycol, glycerin and various similar mixtures of these be able to.

For parenteral administration, sesame or peanut oil or aqueous propylene glycol solutions, as well as corresponding water-soluble superalkali metals or alkaline earth metals. Aqueous solutions of salts can be used. Such aqueous solutions may be buffered with suitable buffers if necessary. and the liquid diluent must first be diluted with sufficient saline or glucose. Make it homodominant. These individual aqueous solutions can be injected intravenously, intramuscularly, subcutaneously and intraperitoneally. Particularly suitable for All sterile aqueous media used in this connection are well known to those skilled in the art. can be easily obtained by standard methods.

For topical administration, dilute sterile aqueous solutions (usually about 0.1-5% concentration) or Manufactured similar to an oral solution in a container suitable for administration in drops to the eye .

In pharmaceutical compositions containing formula r or a pharmaceutically acceptable salt thereof, the carrier versus the active ingredient is The weight ratio is usually 14 to 41, preferably 12 to 21.

However, in any case, the ratio chosen will depend on the solubility of the active ingredient, the intended will vary depending on factors such as dosage and exact route of administration.

The present invention is not limited to the particular embodiments shown, but rather is limited to the scope of the claims. this! FT scales may be varied without departing from the spirit and scope of current ideas. Of course, this is true.

Example 16.7-Sihytroxyindan-1-one in dichloromethane (5 ml) Cold solution of 6.7-nmethquinindan-1-one (0°2 g, 1, Ommol) Boron tribromide was added to the stirred solution at 0'C. After 0.5 hours, the reaction mixture was poured over water. and extracted with EtOAc. Wash the organic layer with brine and dry with Na. 2 SO-) and concentrated in vacuo. Recrystallize the residue from toluene The title compound (0.8 g) was obtained: melting point 141-143 °C (Horne melting point according to Liebigs Ann, 1963.661.44 137℃).

The following compound was prepared using the procedure used to prepare 6,7-hydroxyindan-1-one. Manufactured 4-Bromo-6,7-simethoxyindan-1-one, melting point 180-182°C ( toluene). Elemental analysis value (theoretical value calculated as gH7Br03 C, 44 ,47:H,2,90,Experimental value・C144,76;H,2,91°4-nitro- 6,7-Simethoxyindan-1-one; melting point 202-204°C, setone/Et OAc), elemental analysis value: C9H7NO5" Calculated as 0.25H20 7 ’, = theoretical value C, 50, 62, H, 3, 54: N, 6.56° experimental value C05 0,88;H,a,40:N,6.36゜4-N-(4-nitrobenzoyl)a Mino-6,7-cymethoxyindan-1-t; Melting point > 240'C (7 seconds ton/hexane). Elemental analysis value: C16H12N206・0.75H20 Theoretical value calculated by C, 56, 23; H, 3, 98, N, s, 19° Experimental value C, 56,45; H, 3,52, N, 7.88°4-N-(4-(trifluoro Methyl)benzoyl)amino-6,7-nomethquininodanol-1-one, melting point 1 75°C decomposition (EtOAc/hexane). Elemental analysis value C1□H1□F, NO,・ Theoretical value calculated as #+ as 0.75H20 0.5597:8. 3. 73: N, 3. 84° Experimental value C, 55, 86, H, 3, 30: N, 3. 93° 4-N-(1(t-butyl)benzoyl)amino-6,7-shiftquininodan -1-one, mp 224-226°C (EtOAc/hexane). Elemental analysis value Theoretical value calculated as C9H7NO5.0.5H20 C, 68,95; H.

6.36: N, 4.02° Experimental value C, 68, 70: H, 6, 12; N, 4.　 07° 4-N-(4-(sulfonylmethyl)benzoyl)amino-6,7-simethoxy Indan-1-one, mp 157-159°C (acetone/hexane).

4-N-Hensylamino-6,7-cymethoxyindan-1-one, melting point 12 8-130℃(EtOAc/hexane)・4-N-(phenylsulfonylaminamide) 7-Simethoxyindan-1-one, melting point 242-244°C (EtoA c/hexane).

4-N-((4-nitrophenyl)sulfonyl)amino-6,7-simethoxyi Dandan-1-one, melting point>250°C (EtOAc).

4-N-((t-butylphenyl)sulfonyl)amino-6,7-simethoxyi Ndan-1-on! ! at a point of 126-128°C (EtOAc/hexane ).

4-N-((4-iodophenyl)sulfonyl)amino-6,7-simethoxyi Ndan-1-one, mp 195-198°C (EtOAc/hexane).

4-N-(((4-acetamido)phenyl)sulfonyl)amino-6,7-cy Methoxyindan-1-one, melting point >250'C (acetone/hexane).

4-Benzoyl-6,7-simethoxyindan-1-one, melting point 168-170 °C (EtOAc/hexane), elemental analysis value C+aHtzO4.0. lH2O and Theoretical value calculated as C, 71,15; H, 4,56° Experimental value C, 70,9 1:H, 4, 90° 4-Butanoyl-6,7-cymethoxyindan-1-one, melting point 115-117 °C (EtOAc/hexane).

4-(3-phenylpropionoyl)-6,7-simethoxyindan-1-one , melting point 144-146°C (CHCI3). Elemental analysis value C+ s H+ 60 Theoretical value calculated as 4.0°5H20 C, 70, 81, H, 5, 45° Actual Experimental value C170, 44:H, 5, 10° 4-(3-chenoyl)-6,7-cymethoxyindan-1-one, melting point 174 -176°C (EtOAc/hexane).

4-(2-hydroxybenzoyl)-6,7-simethoxyindan-1-one, Melting point 168-170°C (EtOAc/hexane).

6.7-Simethoxy 1-oxoindan-4-carboxylic acid: melting point>240S, O. DeSilva et al., Can, J. Chem, 1979.57.1598. Manufactured according to the procedure.

Production B 6.7-Simethoxyindan-1-one S, O, DeSilva et al., C Produced according to the procedure of J. Chem., 1979.57.1598.

Preparation C4-21-o-5,7-Simethoxyindan-1-one Stirred Preheated 3-(2-nitro-4,5-dimethoxyphenyl) to the polyphosphoric acid (60 g) Propionic acid (Wa Ike r, G, N, J, Amer, Chem, S oc,, 1956.78.3698.3. 0 g, 12 mmol) was added.

After 2 hours, the reaction mixture was poured onto water and extracted with EtOAc. The organic layer was washed with water, IN Wash with sodium hydroxide, brine and dry. and concentrated in vacuo. Flash chromatography of the residue revealed the title A compound was obtained: melting point 132-134°C. Elemental analysis value Ct + H1t N Theoretical value calculated as O5: (,55,70:H,4,67;N,s,90 ．． Experimental value C, 55, 72: H, 4, 59: N, s, 75° VJD 4-amino-6,7-cymethquinindanol-1-one 4-nitro-6, 7-Simethoxyindan-1-one (10 g, 4.2 mmol) and 10% Pack a mixture of palladium-supported carbon (0.3g)! Hydrogenated for 5 hours (5 0psi). The reaction mixture was filtered through Celite, the filtrate was concentrated in vacuo, and the filtrate was concentrated in vacuo. The residue was recrystallized from EtOAc to give the title compound.

Melting point 178°C0 Elemental analysis value - CllH13N O! Theoretical value calculated as C96375; H, 6, 32; N, 6.76° Experimental value C, 63, 20; H, 6 , 12: 4-N-(4-nitrohendiyl)amide in cyclomethane (40 ml) No-6゜7-simethoxyindan-1-one (06g, 2, 9 mmol) and triethylamine (0.6 ml, 4.3 mmol), chloride Added to a solution of 4-nitrohendiyl (06 g, 3, 7 mmol). 0. After 5 hours, the reaction mixture was poured into INN sodium hydride and extracted with EtOAc.

The organic layer was washed with brine, dried with N a 2 S o +), and dried in vacuo. It was concentrated with The obtained solid was recrystallized from acetone to give the title compound (0.5 g) was gotten. Melting point 220-222°C0 Elemental analysis value CuH+5Nzoa' 0. As 5H20, total 1 [shu theoretical value: C, 59, 17, H.

4, 69; N, 7. 67° Experimental value: C, 59, 29; H, 4, 50; N, 7.　57゜ The following compound (prepared F-N) was prepared using the procedure described above. (lifluoromethyl)benzoyl)amino-6,7-simethoxyindan-1-o Melting point 226-228°C (acetone).

4-N-(4-(t-butyl)henshiyl)amino-6,7-simethoxyinda -1-one, melting point 226°C (EtOAc).

4-N-(4-(sulfonylmethyl)benzoyl)amino-6,7-simethoxy Indan-1-one, melting point 202-203°C (acetone).

4-N-Hensylamino-6,7-cymethoxyindan-1-one, melting point 15 8-159°C (EtOAc/hexane).

4-N-(phenylsulfonyl -one, melting point 184-185°C (MeOH).

4-N-((4-nitrophenyl)sulfonyl)amino-6,7-shiftkin Dandan-1-one, melting point 140-143°C (EtOAc).

4-N-((t-butylphenyl)sulfonyl)amino-6,7-shift key Indan-1-one, melting point 209-211°C (EtOAc). Elemental content Theoretical value calculated as analytical value C2 1 H2 = NO = S.　 62. 51:H. 6. 25:N3 47. Experimental value: C. 62. 22: H. 6. 17:N. 2. 31.

4-N-((4-iodophenyl)sulfonyl)amino-6,7-shiftkin Dandan-1-one, melting point 207-209°C (EtOAc).

4-N-(((4-acetamido)phenyl)sulfonyl)amino-6, 7-Simethoxyindan-1-one, melting point 250°C (THF/E tOA c).

Production 0 4-hexyl-6,7-cymethoxyindan-1-onetoluene (4 4-bromo-6,7-shiftquinindan-1-one (0.5 g, 1. 8 mmol), ethylene glycol (2011) and p-toluene A mixture containing sulfonic acid (10 mg) was refluxed for 10 hours with removal of water ( Dean-Stark Tranop). The reaction solution was diluted in EtOAc to 10% Aqueous sodium hydrohydrogen, washed with water and dried and concentrated in vacuo to give the ethylene ketal as a light brown solid (0.6 g). : Melting point: 100-104°C. This ketal (1. 5g, 4. 7 mmol) in THF (20 ml). Stirring of tium (2.5M in hexane, 2.1 ml, 5, 2 mmol) Warm blood was stirred into a cooled (-789C) solution. After 0.5 hours, benzaldehyde (1, Owl, 9. 4 mmol) was added at once. After another 1 hour at -78°C, the reaction The solution was poured into brine, strained and extracted with EtOAc. Wash the organic phase with brine dry, concentrate in vacuo, and evaporate the residue. After chromatography (50% EtOAc/hexane), it was found that A ton of carbinol (1.3 g) was obtained. DMSO (60ml) This carbinol (12 g, 3.5 mmol) and triethylamine in (4.9 ml, 35 mmol) of pyridine sulfur trioxide complex (17 g, 11 mmol) was added. After 1 hour, the reaction solution was diluted with 10% aqueous sodium hydrogen sulfate. Pressurize with thorium, dissolve with EtOAc, and bring the reaction solution to 0. Stirred for 5 hours . The reaction mixture was poured into brine and extracted with EtOAc. Wash the organic phase with brine. The solution was washed, dried with Na2so, and concentrated in vacuo. 7 residues/Tsyuchroma (50% EtOAc/hexano) to give the title compound. , melting point 117-119°C (Et OAC/hexane).

The following compounds (Preparation P-S) were prepared using the procedure described above: 4-butanoyl-6 , 7-nmethoxoindan-1-ono, melting point 85-87°C.

4-(3-phenylpropionoyl)-6,7-shiftquinindan-1-ono ．． oil.

4-(3-chenoyl)-6,7-nomethoxyindan-1-one, oil.

4-(3-methoxyhenduyl)-6.7-cymethoxyindan-1-one, fused Point 96-98°C (ether). Elemental analysis value - Calculated as C19HIIIOS Theoretical value C. 69.93;H. 5.56. Experimental value C. 70. 02:H ．． 5. 23.

'! R spasm T 6. 7-Simethoxy 1-oxoindan-4-carboxylic acid TH n-butyllithium (2.5M in hexane, 0.5M in hexane) in F (2 ml) ml, 1.3 mmol) of THF (4 ml) to a stirred and cooled (-78°C) solution of The ethylene ketal of 4-bromo-6,7-simethoxyindan-1-one ( 0.35g, 1.

A solution of 11 mmol (see molding procedure above) was added over 10 minutes. moreover After 45 minutes, the reaction solution was poured onto solid carbon dioxide (20 g) and left open for 1 hour! did . The reaction mixture was diluted with ether and extracted twice with water. The combined organic phases were diluted with 6N- Acidify with HC1, dry with N2SO4) and concentrate in vacuo. , and the resulting solid was recrystallized from EtOAc/hexane to yield the title compound. (0.15 g) was obtained.

Melting point>230℃. Elemental analysis value C I 2 H l 2 0; Theoretical value C. 6101;H. s. 12. Experimental value C. 60.96;H. s. 1 9.

Manufacture U 6,7-C (trimethylsiloxylaindan-1-one 6,7-'; Hydroxyindan-1-one (0.3g, 1.8mmol), hexa A mixture of methyldisilazane (4 ml) and 1 sulfuric acid (1 drop) was added at 125°C. Heated for 2 hours. The reaction solution was concentrated in vacuo to give a dark oil. child This was used in the next step without further HE4 treatment.

Production V 2-henshiyl-6,7-sihytroxyindan-1-one THF ( Stirring of diisopropylamine (0.6 ml, 4, 2 mmol) in To a stirred cooled (-78 °C) solution was added n-butyllithium (1.7 ml) in hexane. ,4. A 2.5M solution of 2 mmol 1) was added. After 15 minutes, THF (4ml) of the cycilyl derivative (prepared above) was added over 5 minutes and the reaction solution was The solution was maintained at -78°C for 45 minutes. Hensyl chloride (0.2ml, 2.0 mmoL) was added, and after 15 minutes, the reaction solution was poured into IN-HC. this mixture was extracted with EtOAc, the organic phase was concentrated in vacuo, and the resulting oil was dissolved in THF (5 m ]. )/water (1 ml)/48% aqueous hydrofluoric acid (0.2 ml). 2 After 0 min, the reaction solution was taken up in EtOAc, washed with brine, and dried with Na2 S oJ, concentrated in vacuo. The residue was subjected to flash chromatography (2 5% acetone/hexane) yielded the title compound (0 total).

3g), melting point 144-146°C. Elemental analysis value・Cls Hl2 Theoretical value calculated as 0.4C. 71. 63;H. 4. 51. fruit Experimental value C. 71. 68:H, 4, 52.

The following compounds (preparations W-Z and AA and AB) were prepared using procedure 1 [i] above. Built.

2-(3-promohenzoyl)-6,7-cyhydroxyindan-1-one, fused Point 176-178°C. Elemental analysis value Calculated as C1aH++Br04 Theoretical value C. 55.36:H. 3.19. Experimental value C, 55.26; H. 3.23 .

2-((4-trifluoromethyl)hensyl)-6,7-cyhydroxyinda -1-one, melting point 188-190°C (MeOH), elemental analysis value C,,H ．． 1F, 0. Theoretical value calculated as C, 60, 72; H, 3, 30° Experimental value C160,34:H,3,33° 2-(4-methoxybenzyl)-6,7-cyhydroxyindan-1-one, Melting point 191-193℃ (MeOH), elemental analysis value: Calculated as C17H1405 Calculated theoretical value: C, 68, 45: H, 4, 73° Experimental value: C, 68, 03; H .

4.73° 2-((2,3,4,5,6-bentafluoro)benzoyl)-6,7-schich Droxyindan-1-one: melting point 114-115°C (MeOH). Elemental analysis value :　C16H7FSO4・IHzO and rtt calculated letter theory 1i: C, 50, 4 1,H,2゜37゜Experimental value C,50,41;H,1,96゜2-acetyl-6 ,7-hydroxyindan-1-one: melting point 159-160°C (CHCL3) . Elemental analysis value C1H1°0. Theoretical value calculated as C954,07,H, 4,90° Experimental value C, 63,38; H, 4,83° 2-(2-furanoyl)- 6,7-cyhydroxyindan-1-one: melting point 184.5-185°C ((HC 13/hexane). Elemental analysis value: Theoretical value calculated as C14HI005 C , 65, 11; H, 3, 91° Experimental value: (, 64, 75, H, 3, 56° Manufacture AC2-((2-furanyl)methylene)-6,7-cyhydroxyindan- 1-on Diisopropylamine (0.3 ml, 2, 1 mm) in THF (4 ml) Hexane (0.8 ml, 2,0 m A 2.5M solution of n-butyllithium in mol) was added. After 15 minutes, THF 6,7-di(trimethylsiloxy)indan-1-one (0,4 7 g, 152 mmol) was added over 5 minutes. After another 45 minutes, 2 -furaldehyde (0.25 ml 1.3.04 ml Ilol) was added. 15 After minutes, the reaction solution was poured into IN-HCl and extracted with EtOAc. Organic layer in vacuum Concentrate with THF (5a+1) / HzO (1 ml) / 48% aqueous fluoridated water Stirred for 0.5 h in a mixture of basic acids (0.2 ml). Reaction solution to EtOAc Add, dilute, wash with brine, dry N az S 04), and Concentrated in vacuo. The residue was purified by flash chromatography (30% acetone/ Hexane) to give the title compound as a yellow solid (35 mg).

Melting point 177-179°C.

Manufacture AD 2-bromo-6,7-dihydroxyindan-1-one Be l l Hand of Tetrahedron, 1983.39.2803 by amy, F, D, etc. 10! Manufactured according to.

Production AE 3-phenyl-6, fusihydroxyindan-1-one copper iodide ( I) (0.4 g, 2, 1 mmol) and diethyl ether (20 ml) with a 1.7M solution of phenyllithium (2.5 ml, 4, 2 mmol) in 6,7-Simethoxy in THF (30a+1) to a stirred cooled (0'C) solution of -IH-indan-1-one (0.4g, 2.1mmol-Be l la my, F, D, etc. Tetrahedron, 1983.39.2803) The solution was heated for 5 minutes. After 1 hour, the reaction solution was poured into IN-HCl and E Extracted with tOAc. The organic layer was washed with brine and dried with NazSO4). and concentrated in vacuo. The residue was purified by flash chromatography (50% EtO Ac/hexane) to give the title compound (0.3 g) as an oil.

The following compounds (Preparation AF) were prepared using the above procedure: 3-n-butyl-6, 7-Simethoxyindan-1-one: melting point 104-105°C0 Submission of translation of written amendment Near B in November 1993.

Claims (26)

[Claims] 1. Compounds represented by the following formula and pharmaceutically acceptable salts and prodrugs thereof : ▲There are mathematical formulas, chemical formulas, tables, etc.▼Formula I (in the formula, R2 has halo, COOH, NOz, H, ▲numerical formula, chemical formula, table, etc.▼, ▲number There are formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ;R3 is H, halo, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ Numerical formulas, chemical formulas, tables, etc. There are ▼Alkyl (C1-C4), ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ and ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Yes; R1 is H, alkyl (C1-C6) or phenyl; R5 is phenyl , phenylalkyl (C1-C3), -NH-phenyl, hydroxyphenyl , -(C1-C4)alkyl or thienyl; R6 is (C1-C5)alkyl; Kyl, nitro, perhaloalkyl (C1-C4), halo, -SO2-alkyl ( C1-C4), H or ▲There are mathematical formulas, chemical formulas, tables, etc.▼; and R7 is H, halo, behaloalkyl (C1-C4), alkoxy (C1-C3) the law of nature, However, at least two of R2, R3 or R4 are H, and R3 and and when R4 is H, R2 cannot be H). 2. 2. The compound of claim 1, wherein R2 and R4 are H. 3. R3 is halo, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼▲Mathematical formulas , chemical formulas, tables, etc. ▼, ▲ mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ mathematical formulas The compound according to claim 2, which has a chemical formula, table, etc. ▼. 4. The compound of claim 3, wherein R7 is H, halo, trifluoromethyl or methoxy. Compound. 5. 5. The compound of claim 4, wherein R7 is in the 3 or 4 position. 6. 2. The compound of claim 1, wherein R2 and R3 are H. 7. 7. The compound of claim 6, wherein R4 is phenyl or n-butyl. 8. 2. The compound of claim 1, wherein R3 and R4 are H. 9. R2 is halo, NO2, -COz alkyl (C1-C4) or COOH 9. The compound of claim 8. 10. 9. The compound according to claim 8, wherein R2 is ▲a mathematical formula, a chemical formula, a table, etc.▼. 11. R5 is phenyl, phenethyl, -NH-phenyl, hydroxyphenyl, 11. The compound of claim 10, which is propyl or thiophene. 12. R5 is phenyl, phenethyl, -NH-phenyl, 2-hydroxyphenyl 12. The compound of claim 11, which is 3-thiophene, propyl, or 3-thiophene. 13. R2 is ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ 9. The compound of claim 8. 14. R2 is ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ 14. The compound of claim 13. 15. R6 is t-butyl, nitro, trifluoromethyl, -SO2-methyl or 15. The compound of claim 14, wherein is H. 16. R2 is ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ 9. The compound of claim 8. 17. R2 is ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ 17. The compound of claim 16. 18. R5 is t-butyl, nitro, iodo, H or -NH▲mathematical formula, chemical formula, table 18. The compound of claim 17, which is ▼CH3. 19. 2. A therapeutic method in mammals comprising a compound of claim 1 in a pharmaceutically acceptable carrier. A pharmaceutical composition for suppressing diseases caused by rosine kinase. 20. tyrosine kinases in mammals suffering from diseases caused by tyrosine kinases. tyrosine kinase, wherein the compound of claim 1 is administered in an amount that inhibits the disease caused by tyrosine kinase. How to control the disease. 21. Formula I: ▲There are mathematical formulas, chemical formulas, tables, etc.▼Formula I (in the formula, R2 has halo, COOH, NO2, H, ▲numerical formula, chemical formula, table, etc.▼, ▲number There are formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ;R3 is H, halo, ▲numerical formula, chemical formula, table, etc.▼, -C(=O)-alkyl (C1-C4), ▲Mathematical formulas, chemical formulas, tables, etc.▼,▲Mathematical formulas, chemical formulas, tables, etc. There is ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼; R4 is H, Al Kyl (C1-C6) or phenyl; R5 is phenyl, phenylalkyl (C1-C3), -NH-phenyl, hydroxyphenyl, -(C1-C4)a alkyl or chenyl; R6 is (C1-C6)alkyl, nitro, perha Loalkyl (C1-C4), halo, -SO2-alkyl (C1-C4), H or is -NH-C(=O)-CH3; and R7 is H, halo, perhaloalkyl (C1-C4), alkoxy (C1-C3) and However, at least two of R2, R3 or R4 are H, and R3 and and when R4 is H, R2 cannot be H) and the formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼II (In the formula, R2, R3 and and R4 are as defined above, and R and R1 are alkyl (C1-C4) or is trialkylsilyl). 22. Compounds of formula II, where R and R1 are alkyl (C1-C4), can be treated by deallation. Deprotection by exposure to a killing agent for 2-24 hours at a temperature of 0°C-50°C, 22. The method of claim 21. 23. The dealkylating agent is a mineral acid, boron tribromide or trialkylsilyl halide. 23. The method of claim 22. 24. Compounds of formula II in which R and R1 are trialkylsilyl can be desilylated deprotection by exposure to an agent at a temperature of 0°C to 100°C for 1 to 12 hours. The method of Section 21. 25. The desilylating agent is HF, HBr, HCl, acetic acid or tetraalkyl fluoride. 25. The method of claim 24, wherein the ammonium is ammonium. 26. R2 and R4 are H, and R3 is ▲There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼or▲There are mathematical formulas, chemical formulas, tables, etc. 26. The method of claim 25, wherein ▼.